Caffeine-Induced Activated Glucocorticoid Metabolism in the Hippocampus Causes Hypothalamic-Pituitary-Adrenal Axis Inhibition in Fetal Rats

Abstract

Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg·d caffeine from gestational days 11–20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.

Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study

“…The hippocampus is the primary negative feedback regulatory center of the HPA axis (36). Additionally, caffeine can enter the fetus and directly inhibit 11β-HSD2 expression in the hippocampus.…”

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

“…Another team has suggested that embryonic caffeine exposure produces an increase in body weight (B10%), alters cardiac function and morphology, and produces long-lasting alterations in DNA methylation (Buscariollo et al, 2014). A third group has focused on the neuroendocrine consequences and found that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes that then propagate transgenerationally (Katayama et al, 1987;Xu et al, 2012a;Xu et al, 2012b).…”

Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

“…The concentrations of serum ACTH and CORT were measured by isotope labeling kit (Morgan, 2012) and ELISA kit (Xu et al, 2012b), respectively, following the manufacturer's protocols. The intra-assay and the inter-assay coefficients of variation for ACTH and CORT determination were 10% and 15%, 5.0% and 7.2%, respectively.…”

“…Furthermore, the caffeine concentration in maternal blood was 254 ± 11 μM (49 ± 2 μg/ml) after intake of 120 mg/kg·d caffeine in our studies (Wang et al, 2013), which is only 1.6 times higher than the clinical signs of intoxication (~30 μg/ml), but did not reach the dose with fatalities (~80 μg/ml). In our previous studies (Xu et al, 2012b), we had used 20, 60 and 180 mg/kg·d of caffeine and observed some multi-index changes in 20 mg/kg·d and a clear dose-effect relationship. To achieve the typical IUGR model, the dose of 120 mg/kg·d caffeine was used, to verify the transgenerational effects in the present study.…”